The present invention relates to a process for producing alkoxyanilines which are useful as an intermediate for medicines and dyes and a raw material for various chemical compounds.
More particularly, it relates to a process for selectively producing alkoxyanilines in high yield and high efficiency by directly reacting hydroxyaniline with an alkyl halide.
It has been difficult to selectively produce the alkoxyaniline [I] by directly reacting hydroxyaniline with an alkyl halide because N-alkyl hydroxyaniline [a] and N-alkyl alkoxyaniline [b] have been formed as the by-products as shown in the following reaction formula [A]. ##STR2##
Accordingly, the alkoxyanilines have been produced by the process (1) which comprises protecting amino group (--NH.sub.2) of hydroxyaniline as acetamide group (--NHCOCH.sub.3) by an acetylation and then alkylating it with an alkyl halide and hydrolyzing it. [Journal of the Pharmaceutical Society of Japan Vol. 74 Pages 872 to 875 and Journal fur Prektische Chemie Vol. 4 No. 1 Pages 57 to 86 (1954)]. ##STR3##
However, the steps of the acetylation and hydrolysis are included in the process (1) and accordingly, the reaction steps are complicated and many steps are needed whereby the cost of the alkoxyaniline is disadvantageously high, and the process is not satisfactory as the industrial process.
It has been studied to use the other alkylating agents instead of the alkyl halide.
As the result, it has been proposed to produce the alkoxyanilines by the process (2) which comprises converting hydroxyl group (--OH) of hydroxyaniline to sulfonic acid ester (--OSO.sub.2 Ar) with sulfochloride (ArSO.sub.2 Cl) and using an alkali metal alcoholate (ROM) as the alkylating agent. [Journal of the Pharmaceutical Society of Japan Vol. 74 Pages 872 to 875 (1954) and Afinidad Organo de la Asocion de Quimicos Vol. 25 Pages 547 to 551 (1948)]. ##STR4##
It has been also proposed to produce the alkoxyanilines by the process (3) which comprises directly alkylating hydroxyaniline with a dialkyl sulfate as the alkylating agent. [Journal of Organic Chemistry Vol. 22, Pages 333 to 334 (1957)]. ##STR5##
However, the sulfochlorides used in the process (2), react with an alcohol and phenol to produce sulfonic esters, and also react with ammonia, a primary amine or a secondary amine to produce sulfamides. Accordingly, in the case of hydroxyaniline having hydroxyl group and amino group, when the sulfochloride is used, the hydroxyl group of hydroxyaniline is converted to the sulfonic acid ester, and the amino group is converted to sulfamide at the same time, as shown in the following reaction formula (2'), whereby N-alkyl hydroxyaniline [a] and N-alkyl alkoxyaniline [b] are produced as the by-products. ##STR6##
The sulfochlorides have stimulative smell and the alkali metal alcoholates as the alkylating agent are expensive and the operation for the reaction and the post-treatment are complicated as the industrial operation and the cost is disadvantageously high. Moreover, two steps are needed in the process (2).
In the process (3), the dialkyl sulfate used as the alkylating agent reacts as the alkylating agent for both of hydroxyl group and amino group whereby N-alkyl hydroxyaniline [a] and N-alkyl alkoxyaniline [b] are produced as the by-products.
Only dimethyl sulfate and diethyl sulfate are easily available as the dialkyl sulfates. Accordingly, the alkylations by the dialkyl sulfates are limited to methylation and ethylation, and it is not easy to give the alkylation for the alkyl group having 3 or more carbon atoms.
Usually, dialkyl sulfates have high toxicity. Though dimethyl sulfate is an active methylating agent, it is highly toxic, and it is not easy to use in the operation because the poisoning is caused by breathing the vapor and absorbing through the skin to cause dermatitis damages and mucous membrane damages.
As stated above, it has been difficult to selectively produce the alkoxyanilines by directly reacting hydroxyaniline with an alkyl halide. Accordingly, various processes have been proposed, however these conventional processes have not been satisfactory as the industrial process.